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Enterohemorrhagic Escherichia coli
Introduction
Escherichia coli (E. coli) is a species of gram-negative, rod-shaped bacteria belonging to the genus Escherichia and commonly residing in the human colon and that of many other animal species. Shigatoxigenic E. coli (STEC) and verotoxigenic E. coli (VTEC) are E. coli strains known to produce Shiga toxin and Shiga-like toxin (verotoxin), respectively. The strains that cause ailments in humans are commonly known as enterohemorrhagic E. coli (EHEC). The terms mentioned above are often used interchangeably. EHEC serotype O157:H7 is a human pathogen found to be responsible for bloody diarrhea outbreaks and postdiarrheal hemolytic uremic syndrome (HUS) worldwide.[1]
Etiology
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Etiology
EHEC is a type of E. coli associated with bloody diarrhea, acute kidney injury, and, in some cases, HUS. E. coli is a gram-negative, rod-shaped bacterium belonging to the genus Escherichia. This organism contains up to 2,000 genes that encode various virulence factors, reflecting the diversity of E. coli clones, including EHEC.[2] E. coli is a facultative anaerobe, measuring 1 to 2 μm in length and 0.5 μm in width, with chemotactic motility. This microorganism commonly colonizes the intestines of all known mammals.[3][4][5]
E. coli is one of the most commonly identified bacteria in the human intestinal microbiota from birth and remains a lifelong colonizer.[6] STEC and VTEC are known to cause human illness. The terms "STEC" and "VTEC" are often used interchangeably with "EHEC." These strains are likely transmitted to humans from the gut colonization of ruminants, particularly farm animals.[7] Humans can become infected through environmental transmission from contaminated food and water or close contact with infected animals or individuals. EHEC serotype O157:H7, a known human pathogen, is responsible for outbreaks of bloody diarrhea and HUS, often associated with contaminated food or environmental sources.[8]
Epidemiology
The Centers for Disease Control and Prevention (CDC) estimates that foodborne E. coli O157:H7 is responsible for over 63,000 illnesses annually, leading to more than 2,100 hospitalizations and deaths in the U.S. For over 20 years, E. coli O157 outbreaks in the U.S. have resulted in 17% of the cohort becoming hospitalized, with 4% resulting in HUS.[9] The economic burden of illness due to this bacterium resulting from medical expenses, death, and loss of productivity is estimated to be $405 million per year.[10]
The 2017 preliminary report from the 10 U.S. sites of the Foodborne Diseases Active Surveillance Network (FoodNet) lists STEC as 1 of the 9 pathogens commonly transmitted by food. Compared to the incidence from 2014 to 2016, the incidence in 2017 was 28% higher. Fifty-seven cases of HUS were identified in 2016, with the incidence remaining not significantly different from 2013 to 2015.[CDC. 2017 Preliminary Data.]
In Norway, HUS is the 2nd most common cause of acute kidney injury in children, with an estimated average annual incidence of 0.5 cases per 100,000 children.[11] For over 10 years, the rates of bloody diarrhea and hospitalization in England have remained stable despite a decline in E. coli O157 and HUS, possibly due to changes in food consumption, food safety, and the availability of animal reservoirs.[12]
The natural reservoir for E. coli O157:H7 is the intestines of ruminants, and outbreaks can occur from ingesting undercooked meat or fomites from manure-contaminated food or water. Contamination can also result from the use of manure as fertilizer or from water supplies contaminated by runoff from cattle farms. Although variation in fecal shedding of E. coli O157:H7 has been reported, ranging from 0% to 80% among the cattle population, a seasonal pattern has been observed, with prevalence increasing during the summer months.[13]
Pathophysiology
Upon entry, EHEC migrates to the gastrointestinal tract, surviving innate host defenses such as saliva, gastric acids, and intestinal mucus using acid resistance mechanisms.[14] The organism targets the Peyer patches and intestinal villi, where it forms pathogenic lesions and colonizes the large intestine.[15] In this environment, virulence factors are upregulated through interactions with short-chain fatty acids secreted by intestinal flora, facilitating further adherence and increasing toxin susceptibility.[16][17]
EHEC strains produce Shiga-like toxins (Stx), which disrupt membrane ion channels in the epithelial membrane of the intestine. This dysregulation leads to ion loss and a massive loss of water, potentially allowing for bacterial translocation and invasion.[18] The toxin also functions as a cell transducer and immune modulator, inducing pro-inflammatory and proapoptotic sequelae. Additionally, this toxin can inactivate 60S ribosomal units, inhibiting protein synthesis in endothelial cells.[19]
Neutrophil numbers rise markedly, and the extent of this increase correlates with a higher occurrence of HUS.[20] Inflammatory monocytes also rise and produce pro-inflammatory cytokines. Shigatoxin-susceptible receptors are present on erythrocytes, platelets, and monocytes.[21][22] Microthrombi may develop due to the interaction between shigatoxin and platelet-leukocyte aggregation. Consequently, activated endothelial cells may become thrombogenic, leading to endothelial lesions in the microvasculature, primarily in the kidneys, and less frequently in other organs, contributing to the development of HUS. Thrombocytopenia, a characteristic feature of HUS pathogenesis, may be linked to the consumption of microthrombi by the immune response. In severe cases, nonimmune microangiopathic hemolytic anemia (MAHA) may occur.[23]
Endothelial dysfunction in the kidneys can result in acute renal impairment. Although the kidney and gastrointestinal tract are the most commonly affected organs in HUS, studies have also shown evidence of central nervous system, pancreatic, skeletal, and myocardial involvement. While the mechanism of microvascular injury is not fully understood, evidence suggests that verocytotoxin plays a role in mediating cell injury, altering the endothelial cell's normal anticoagulant profile to a procoagulant state.[24]
After an E. coli infection, several factors determine the progression of the disease to HUS, including the following:
- Bacterial strain: Serotype O157:H7 is most often responsible for the progression to HUS.
- Age: The rate of progression to HUS is higher in young children. A study found the progression rate to be 12.9% in children under 5 years, 6.8% in children aged 5 to 10 years, and 8% in children older than 10 years.[25]
- Antibiotic therapy: Treatment of E. coli O157:H7 with antibiotics, particularly β-lactams, may increase the risk of developing HUS.
- Environmental factors: Variables, such as proximity to cattle density and rainfall, have been identified in observational datasets. However, such factors should be considered in the context of E. coli transmission.
- Genetic factors: The presence of a platelet glycoprotein 1b α 145M allele has been associated with an increased risk of HUS.[26]
Other factors that may correlate with HUS include a higher leukocyte count and vomiting during the first week of illness.[27] For further information on E. coli pathophysiology, refer to StatPearls' companion topic, "Escherichia coli infection."
Histopathology
In the acute phase of HUS, kidney specimens show microvascular injury, characterized by microthrombi deposition and detached, swollen glomerular endothelial cells associated with inflammatory cell infiltration. Similar changes have been observed in other organs, including the pancreas, adrenal glands, and brain.[28] Autopsy findings have included platelet aggregation, fibrin accumulation, and a low platelet count on factor VIII staining. Areas of ischemia with microscopic angiopathy may be present, and destruction of the renal cortex can occur, showing capillary wall thickening, thrombosis of the capillary lumen, preglomerular arteries, and endothelial cells.[29] Gastrointestinal changes may include mucosal and submucosal edema or hemorrhage.[30]
Toxicokinetics
EHEC is not invasive, making bacteremia rare. This microorganism adheres to mammalian cells and secretes bacterial proteins into host cells via a type III secretion system. Shiga-like toxins 1 (Stx1) and 2 (Stx2) are secreted and responsible for organ damage. Stx2 is more frequently associated with severe disease.[31]
Shiga toxin consists of 2 subunits, A and B. Proteolysis degrades subunit A into A1 and A2. In target organs, such as the kidney, brain, and gut, subunit B attaches to glycolipid receptors on the cell surface. In humans, these receptors are identified as Gb3, primarily expressed in kidney tubular cells, the brain, and gut epithelium. Tumor necrosis factor α amplifies the cytotoxicity in the kidney.[32]
After binding to the cell surface, Shiga toxin is endocytosed and transported in a retrograde direction to the Golgi apparatus and endoplasmic reticulum. From there, the toxin is translocated to the cytosol, where it inactivates ribosomes, leading to cell death.[33] Other virulence factors encoded on plasmids include enterohemolysin (Ehx), which has a cytolytic effect; EspP extracellular serine protease, which cleaves human coagulation factor V; and enteroaggregative E. coli heat-stable enterotoxin 1 (EAST1), which may contribute to the development of STEC diarrhea.[34][35]
History and Physical
A history of exposure to contaminated sources, including food and drinking water, or close contact with ruminants is often reported. EHEC clinically manifests as bloody diarrhea (visibly bloody stool specimen) without fever and typically a white blood cell count above 10,000/μL, sometimes associated with abdominal pain. The incubation period between exposure to EHEC and onset of symptoms is typically 3 to 4 days.[36]
HUS is a major complication of EHEC infection, characterized by the clinical triad of anemia due to hemolysis, impaired renal function, and thrombocytopenia, primarily affecting young children. Anemia typically manifests as pallor on examination, thrombocytopenia as petechial rashes, and a decline in renal function as decreased urine output. However, atypical cases may not present with all these features and may also warrant consideration of alternative diagnoses.[37] HUS following bloody diarrhea secondary to EHEC is called "D+ HUS" or "typical HUS," while HUS caused by other factors is termed "D- HUS" or "atypical hemolytic uremic syndrome" (aHUS).
Evaluation
Patients suspected of EHEC infection are tested for Shiga toxin or EHEC through stool culture, specifically for E. coli O157. Shiga toxin is primarily detected using direct enzyme immunoassay, but the genes for this toxin may also be identified by real-time PCR.[38] Some centers use matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to detect the genes.
Blood and urine tests are also conducted in patients presenting with HUS. These tests can reveal low red blood cell and platelet counts and assess renal function, respectively.[39] Diagnosis relies on excluding other presenting syndromes and infections, as well as considering the patient's history and physical examination findings.
Cultures may be used to isolate EHEC and test for antimicrobial resistance. Due to the risk of Coombs-negative MAHA, a hemolysis screen is warranted in cases of anemia. A blood film may reveal red cell fragmentation, and hypocomplementemia may occur. ADAMST13 does not typically decrease in EHEC HUS, and a reduction in ADAMST13 is more commonly associated with aHUS.[40][41]
Treatment / Management
Supportive treatment is essential for patients with EHEC diarrhea. Replacing electrolytes and water is particularly important for those with D+ HUS, which may be achieved through oral or intravenous fluid and electrolyte administration. Early intervention with close and judicious monitoring of volume and sodium status can help reduce the risk of progressing to oliguric or anuric HUS.[42]
Medications that may exacerbate renal impairment, including antihypertensives, should be withheld during this period, as they can impair renal perfusion.[43] Advancements in dialysis and intensive care have significantly reduced mortality, especially among young children. Up to 2/3 of children infected with EHEC may require dialysis.[44] Peritoneal dialysis is often the best option for children with acute and severe renal impairment and significant bloody diarrhea.
Bilateral nephrectomy may be life-saving in severe cases where the kidneys are the primary site of disease involvement. This intervention can help control the spread of microvascular lesions, particularly in therapy-resistant malignant hypertension.
Given the often severe prognosis, immediate supportive treatment is crucial to improve outcomes. Additional supportive treatments for HUS depend on the patient’s symptoms and may include the following:
- Red blood cell transfusions, particularly in those with anemia
- Plasma exchange [45]
- Fresh frozen plasma
- Eculizumab, particularly in those with neurological manifestations [46]
The effect of plasma exchange is most notable in older adults and children when initiated early in the disease course.[47] Fresh frozen plasma has been employed in rare cases.[48] Eculizumab has also been used for typical HUS with neurological involvement.(B3)
Platelet transfusions are generally contraindicated due to the risk of exacerbating illness. Transfusions may perpetuate platelet aggregation in patients with thrombotic microangiopathy associated with HUS.[49][50] Antibiotics, particularly β-lactams, are relatively contraindicated in EHEC-associated HUS, as they may indirectly cause the release of Shiga toxin from lysed bacteria, resulting in further renal and gastrointestinal injury.[51] The use of β-lactam antibiotics has also been linked to the development of HUS.
Differential Diagnosis
The differential diagnosis for HUS symptoms includes aHUS and thrombotic thrombocytopenic purpura (TTP), which can overlap. AHUS is associated with dysregulated complement activation, while the pentad of MAHA, thrombocytopenia, renal abnormalities, fever, and neurological abnormalities classically characterize TTP.
In patients of unusual age or without a history of diarrhea, anomalous or atypical E. coli HUS should be considered. Acute bloody diarrhea may also suggest other differentials, including inflammatory bowel disease, rectal or colorectal carcinoma, hemorrhoids, and a perforated viscus. Bloody diarrhea can also result from infections caused by other organisms, including Salmonella, Campylobacter, Yersinia, tuberculosis, and Entamoeba.[52]
Prognosis
Early diagnosis of EHEC infection and prompt fluid replacement have been shown to improve long-term outcomes by reducing kidney damage. The volume of appropriate intravenous fluid replacement is directly associated with the risk of developing oliguria and anuria in patients with EHEC-associated HUS. Patients infected with the E. coli O157:H7 serotype are more likely to present with hematochezia and leukocytosis than individuals unaffected by this strain. These patients also tend to require a longer duration of dialysis. Advancements in dialysis therapy and improved interventions for critically ill children have significantly reduced the acute mortality of HUS. However, as survival rates improve, chronic complications in long-term survivors are becoming increasingly apparent.[53]
Complications
EHEC-associated bloody diarrhea often resolves without long-term consequences. However, the prognosis is severe in patients who develop HUS. Following treatment for HUS, some children may experience permanent loss of renal function, necessitating long-term renal replacement therapies. Even patients who recover baseline renal function remain at risk for the late onset of renal disease. Residual extrarenal complications may occur in some children, including neurological defects, insulin-dependent diabetes mellitus, pancreatic insufficiency, and gastrointestinal problems.[54] HUS is thus associated with significant mortality and multisystem morbidity. Attention should be given to extrarenal manifestations during the acute phase, and renal function should be closely monitored during the long-term follow-up of patients with HUS.[55]
Deterrence and Patient Education
Implementing measures such as using drinkable water for food preparation, maintaining improved hygienic conditions during animal slaughter, adopting appropriate food processing techniques, properly cooking food, and educating food handlers and farm workers on food hygiene principles can significantly reduce the incidence of EHEC infections. Preventing foodborne diseases generally relies on good hygienic practices and controlling food contamination by biological and chemical hazards. Patients and their families should be counseled on preventative strategies, which can be effectively communicated through food safety guidelines. Vaccines for EHEC are under study but have not yet been approved by the Food and Drug Administration.
Pearls and Other Issues
EHEC is a foodborne disease that may be mitigated by practicing good hygiene and controlling food contamination. Public health and food standards authorities play a crucial role in regulating and monitoring safety related to foodborne contamination. In some jurisdictions, EHEC constitutes a public health notifiable condition. This human pathogen has been identified as a cause of bloody diarrhea outbreaks and HUS globally. Specific treatment options are unavailable, and therapeutic measures remain supportive.
Enhancing Healthcare Team Outcomes
The management of EHEC requires an interprofessional team approach. Close fluid and electrolyte monitoring, facilitated by attentive nursing and medical care, is crucial for the early detection of clinical deterioration. Supportive treatment is sufficient for most patients, with particular attention to replacing electrolytes and water deficiencies, especially in those with D+ HUS.
Advancements in dialysis and intensive care have significantly reduced mortality, particularly in young children, where peritoneal dialysis may be necessary to manage severe complications. Surgical intervention, including bilateral nephrectomy, may be life-saving in severe cases. This procedure can help control the spread of microvascular lesions when the kidneys are the primary site of disease involvement, particularly in therapy-resistant malignant hypertension.
Given the potential severity of the prognosis, immediate supportive treatment may improve outcomes. Additional supportive treatments for patients with HUS are largely symptom-dependent and may include blood transfusions and, in rare cases, plasma exchange.
Public health clinicians should be notified of cases to facilitate contact tracing and environmental investigations. Collaboration with local government and food safety authorities is essential to identify and mitigate sources of exposure.
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